Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A kinase cascade highly conserved throughout evolution, Raf/MAP kinase kinase kinase (MAPKKK)-->MAP kinase kinase (MAPKK)-->MAP kinase (MAPK)-->ribosomal S6 kinase (p90 RSK), is thought to play a crucial role in signal transduction from the membrane to the nucleus. In mammalian cells, this cascade is connected both to tyrosine kinase receptors and G protein-coupled receptors. Although the mode of activation at the receptor level differs, all mitogens activate the ubiquitously expressed isoforms of MAPK, p42 and p44. We have cloned, epitope tagged and expressed in fibroblasts, the Hamster MAPKK and p44 MAPK in order to analyze their time-course of activation, their subcellular localization, their regulatory phosphorylation sites and their role in cell cycle entry. We have demonstrated that MAPK activation was rapid, biphasic and persistent. The sustained phase of activation is only obtained with potent mitogenic agents, correlating with their ability to elicit cell cycle entry. Activation of MAPKK is also rapid and persistent but does not distinguish between mitogenic and non mitogenic factors, indicating that a distinction occurs at the MAPK level, probably by the action of specific phosphatases such as MAPK phosphatase MKP-1. Both isoforms of MAPK are translocated into the nucleus upon growth factor addition whereas the upstream activators (MAPKKK, Raf and MAPKK) remain cytoplasmic. MAPK translocation, together with the ability of MAPK to phosphorylate transcription factors, indicates that MAPK might constitute a relay between cytoplasmic and nuclear events. Finally we show that interfering with the MAP kinase cascade, by expressing either MAPK antisense, a MAPK dominant negative mutant or the MAPK specific phosphatase, MKP-1, suppresses the growth factor induced G0 to G1 transition. In addition, permanently activated versions of MAPKK reduce growth factor requirement, allow autonomous cell growth and induce tumor formation in nude mice. We therefore conclude that MAP kinase activation is both necessary and sufficient to trigger cell cycle entry.
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PMID:[MAP kinase module: role in the control of cell proliferation]. 764 66

Activation of tyrosine kinase receptors causes mitogen-activated protein (MAP) kinase stimulation via a pathway involving p21ras, p74raf-1 (acting as a MAP kinase kinase kinase), and MAP kinase kinases; however, the pathway by which heterotrimeric G-protein-coupled receptors activate MAP kinases is undefined. Since there are several MAP kinase kinase kinases it has been suggested that p74raf-1 may only couple tyrosine kinase receptors to MAP kinase activation. We therefore investigated the requirement for p21ras and p74raf-1 in G-protein receptor-mediated MAP kinase activation. Lysophosphatidic acid stimulates MAP kinase via a pertussis toxin-sensitive pathway, which is blocked by dominant negative Ras. Lysophosphatidic acid-stimulated MAP kinase activation is potentiated by overexpression of p74raf-1 and blocked by expression of a dominant negative Raf protein comprising the N-terminal 259 amino acids. We conclude that lysophosphatidic acid activates MAP kinases by a G-protein-coupled pathway that requires both p21ras and p74raf-1.
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PMID:Lysophosphatidic acid stimulates mitogen-activated protein kinase activation via a G-protein-coupled pathway requiring p21ras and p74raf-1. 840 93

The leukemogenic tyrosine kinase fusion protein Bcr-Abl activates a Ras-dependent pathway required for transformation. To examine subsequent signal transduction events we measured the effect of Bcr-Abl on two mitogen-activated protein kinase (MAPK) cascades--the extracellular signal-regulated kinase (ERK) pathway and the Jun N-terminal kinase (JNK) pathway. We find that Bcr-Abl primarily activates JNK in fibroblasts and hematopoietic cells. Bcr-Abl enhances JNK function as measured by transcription from Jun responsive promoters and requires Ras, MEK kinase (MAPK/ERK kinase kinase), and JNK to do so. Dominant-negative mutants of c-Jun, which inhibit the endpoint of the JNK pathway, impair Bcr-Abl transforming activity. These findings implicate the JNK pathway in transformation by a human leukemia oncogene.
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PMID:The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. 852 41

The pertussis toxin (PTX) insensitive heterotrimeric G protein G12 has been implicated in mitogenesis and transformation, but its direct effectors remain unknown. To define potential signaling pathways utilized by G12, we expressed an activated mutant of its alpha subunit, Galpha12(Q229L), in HEK293 cells and examined its effects on Ras and mitogen-activated protein kinases (MAPKs). Transient expression of activated Galpha12 increased the percentage of Ras in the active, GTP-bound state, stimulated c-Jun NH2-terminal kinase (JNK) activity, and enhanced the transcriptional activity of c-Jun. Dominant negative Ras (N17Ras) inhibited Galpha12-mediated JNK activation in NIH3T3 cells but failed to do so in HEK293 cells. In contrast, dominant negative Rac (N17Rac1) inhibited JNK activation by Galpha12 in HEK293 cells as well as three other cell lines. In 1321N1 cells, where thrombin stimulates G12-dependent mitogenesis, coexpression of N17Rac1 or a dominant negative mutant of MEKK1 (MEKKDelta(K432M)) inhibits c-Jun/AP-1 sensitive reporter gene expression stimulated by thrombin or Galpha12. These data demonstrate that the alpha subunit of the heterotrimeric G protein G12, like tyrosine kinase growth factor receptors, activates Ras and recruits a signal transduction pathway involving the small GTP-binding protein Rac that leads to JNK activation.
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PMID:Galpha12 stimulates c-Jun NH2-terminal kinase through the small G proteins Ras and Rac. 866 28

While activation of tyrosine kinase growth factor receptors is accompanied by hyperphosphorylation of Raf-1, stimulation of receptors coupled to G-proteins has in some cases been shown to result in activation of a non-Raf MEKK rather than of Raf itself. Our finding (Weiss, R. H., and Nuccitelli, R. (1992) J. Biol. Chem. 267, 5608-5613) that the thrombin receptor requires tyrosine phosphorylation for its mitogenic effect in vascular smooth muscle cells led us to search for the molecules which are being tyrosine phosphorylated by this receptor. To determine whether mitogenic signalling of G-protein-coupled growth factor receptors results in tyrosine phosphorylation of Raf, we examined activation of Raf by two such receptors. Both thrombin and angiotensin II are mitogenic in NIH3T3 cells, but only thrombin causes hyperphosphorylation of Raf-1. Activation of Raf by thrombin is associated with phosphorylation of Raf-1 on tyrosine residues, whereas activation of Raf by angiotensin II does not involve significant tyrosine phosphorylation. However, Shc is tyrosine phosphorylated by both thrombin and angiotensin II. Thus, there exists a divergence in the mitogenic signalling pathways of the G-protein-coupled receptors relative to the Raf signalling cascade. While both thrombin and angiotensin II phosphorylate Shc and activate Raf catalytic activity, only thrombin phosphorylated Raf-1 on tyrosine. This signalling through disparate Raf-coupled pathways suggests one means by which the G-protein-coupled receptors may confer specificity in their signalling properties.
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PMID:Divergence in the G-protein-coupled receptor mitogenic signalling pathway at the level of Raf kinase. 937 25

The signaling of ligands operating via heterotrimeric G proteins is mediated by a complex network that involves sequential phosphorylation events. Signaling by the G protein-coupled receptor GnRH was shown to include elevation of Ca2+ and activation of phospholipases, protein kinase C (PKC) and extra-cellular signal-regulated kinase (ERK). In this study, GnRH was shown to activate Jun N-Terminal Kinase (JNK)/SAPK in alpha T3-1 cells in a PKC- and tyrosine kinase-dependent manner. GnRH as well as tumor-promoting agent (TPA) also increased c-Src activity, which peaked at 2 min after GnRH stimulation and was sensitive both to PKC and to tyrosine kinase inhibitors. Coexpression of Csk, which serves as a Src-dominant interfering kinase, and constitutively active forms of Src, together with JNK, confirmed the involvement of c-Src downstream of PKC in the GnRH-JNK pathway. Coexpression of dominant negative and constitutively active forms of CDC42, Rac1, Ras, MEKK1, and MEK1 with JNK indicated that JNK activation by GnRH and TPA is mediated by CDC42 and MEKK1. Ras and MEK1, which are involved in a related mitogen-activated protein kinase (MAPK) pathway, did not affect JNK activation in alpha T3-1 cells. Taken together, our results suggest that GnRH stimulation of JNK activity is mediated by a unique pathway that includes sequential activation of PKC, c-Src, CDC42, and probably also MEKK1.
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PMID:Stimulation of Jun N-terminal kinase (JNK) by gonadotropin-releasing hormone in pituitary alpha T3-1 cell line is mediated by protein kinase C, c-Src, and CDC42. 962 57

Ethanol increases human and animal susceptibility to opportunistic lung infections in part by suppression of endotoxin (LPS) and bacteria-mediated upregulation of inducible nitric oxide synthase (iNOS) in alveolar macrophages (AM). LPS and cytokine-induced NOS mRNA are dependent on NF-kappaB/Rel (NFkappaB) and Activator Protein-1 (AP-1), which are regulated in turn by protein kinase C and tyrosine kinase-dependent phosphorylation. ETOH does not directly inhibit NFkappaB or AP-1, in vivo, but rather inhibits LPS-induced activation of the MEKK/MAP kinase system and inhibition of inhibitory protein IkappaBalpha required for formation of AP-1 and NFkappaB, respectively. in AM. Both transcription factors are involved iNOS mRNA transcription. LPS-induced upregulation of MEKK/MAP tyrosine kinase upregulates NADPH oxidase activity and oxygen free radical formation required for activation of NFkappaB and AP-1 and phosphorylation of IkappaBalpha. LPS downregulates endogenous calcium-sensitive PKC isozymes (PKCdelta), which repress iNOS mRNA expression. ETOH inhibits LPS-induced upregulation of iNOS mRNA by preventing its ability to decrease PKCdelta and upregulate tyrosine kinase-mediated phosphorylation. This effect of ETOH is prevented by inhibitors of PKC and tyrosine kinase. The data support the hypothesis that ETOH inhibits LPS-induced upregulation of iNOS mRNA by interfering with the phosphorylation processes involved in activation of the nuclear transcription factors NFkappaB and AP-1.
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PMID:Role of PKC and tyrosine kinase in ethanol-mediated inhibition of LPS-inducible nitric oxide synthase. 966 19

Hepatocellular carcinoma (HCC) is one of the major causes of human cancer deaths worldwide. To identify alterations of the genetic program associated with human HCC, we designed a new protocol based on the high-density replica method to analyze protein kinase gene expression in normal liver, HCC, and HCC-derived cell lines. RNA was prepared for reverse transcription and cDNA was used for PCR amplification of the conserved catalytic domain of protein kinase genes. Initially, from a pair of HCC and the adjacent noncancerous tissues, we sequenced 228 samples and identified 26 genes that represent different tyrosine kinase subfamilies. High-density grid filters were then prepared to assist the identification, by hybridization, of genes that are differentially expressed in normal vs HCC samples. Eleven tyrosine kinase genes were tested, and positive signals were reliably scored by doubly offset duplicates and by two independent gene-specific probes. Of the 11 genes tested, PDGF receptor-beta, MEKK-3, axl, and FGFR-4 are preferentially expressed in tumor samples. Additionally, we analyzed protein kinase gene expression in five HCC cell lines and identified distinct kinase gene expression patterns in different cell lines. Our results suggest that multiple kinases are activated in different tumors and confirm that there is molecular heterogeneity in the mechanisms sustaining autonomous cell growth in liver tumor formation.
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PMID:Parallel hybridization analysis of multiple protein kinase genes: identification of gene expression patterns characteristic of human hepatocellular carcinoma. 967 27

Involucrin is a marker of keratinocyte terminal differentiation. Our previous studies show that involucrin mRNA levels are increased by the keratinocyte differentiating agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) (Welter, J. F., Crish, J. F., Agarwal, C., and Eckert, R. L. (1995) J. Biol. Chem. 270, 12614-12622). We now study the signaling cascade responsible for this regulation. Protein kinase C and tyrosine kinase inhibitors inhibit both the TPA-dependent mRNA increase and the TPA-dependent increase in hINV promoter activity. The relevant response element is located within the promoter proximal regulatory region and includes an AP1 site, AP1-1. Co-transfection of the hINV promoter with dominant negative forms of Ras, MEKK1, MEK1, MEK7, MEK3, p38/RK, and c-Jun inhibit the TPA-dependent increase. Wild type MEKK1 enhances promoter activity and the activity can be inhibited by dominant negative MEKK1, MEK1, MEK7, MEK3, p38/RK, and c-Jun. In contrast, wild type Raf-1, ERK1, ERK2, MEK4, or JNK1 produced no change in activity and the dominant negative forms of these kinases failed to suppress TPA-dependent transcription. Treatment with an S6 kinase (S6K) inhibitor, or transfection with constitutively active S6K produced relatively minor changes in promoter activity, ruling out a regulatory role for S6K. These results suggest that activation of involucrin transcription involves a pathway that includes protein kinase C, Ras, MEKK1, MEK3, and p38/RK. Additional pathways that transfer MEKK1 activation via MEK1 and MEK7 also may function, but the downstream targets of these kinases need to be identified. AP1 transcription factors appear to be the ultimate target of this regulation.
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PMID:Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. 973 28

Raf-1 activation and Bcl-2 hyperphosphorylation following treatment with paclitaxel (Taxol) or other microtubule-active drugs is associated with mitotic arrest. Here we show that microtubule-active drugs do not activate the mitogen-activated protein kinase (MAPK) pathway in leukemia cells. PD98059, a MEK inhibitor, and SB202190, a p38 MAP kinase inhibitor, do not abrogate Bcl-2 phosphorylation nor apoptosis. Simultaneously with PARP cleavage, paclitaxel induces cleavage of Bcl-2 protein yielding a potentially pro-apoptotic 22 kDa product. In comparison, the stimulation of Raf-1 by phorbol ester (TPA) activates the MAPK pathway, causes MAPK-dependent p21WAF1/CIP1 induction, Rb dephosphorylation and growth arrest without Bcl-2 phosphorylation or apoptosis. Like TPA, cAMP induces p21WAF1/CIP1 but does not cause Bcl-2 phosphorylation. MEKK1 and Ras, upstream activators of JNK and ERK MAPK, also fail to induce Bcl-2 hyperphosphorylation. Although Lck tyrosine kinase has been recently implicated in Raf-1 activation during mitotic arrest, microtubule-active drugs induce Raf-1/Bcl-2 hyperphosphorylation and apoptosis in a Lck-deficient Jurkat cells. Therefore, microtubule-active drugs induce apoptosis which is associated with Raf-1 and Bcl-2 phosphorylation and Bcl-2 cleavage but is independent of the MAPK pathway. In contrast, TPA-activated MAPK pathway causes p21WAF1/CIP1-dependent growth arrest without apoptosis.
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PMID:Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells. 1040 Apr 18


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